9-halo-12-alkyl-11-oxygenated progesterones



United States Patent 3,151,135 9-HALtJ-12-ALKYL-lI-OXYGENATED PRGGESTERONES Gordon H. Thomas, Birmingham, England, and Josef Fried, Princeton, NJ assign-tars to 01in Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Sept. 13, 1962, Ser. No. 224,529 4 Claims. (Cl. 26t9--397.45)

This application is a continuation-in-part of our application, Serial No. 860,733, filed December 21, 1959, now abandoned, which in turn is a continuation-in-part of our application, Serial No. 711,779, filed January 29, 1958, and now abandoned.

This invention relates to the synthesis of steroids and has for its object the provision of new steroids of the general formula wherein the 1,2-position is saturated or double-bonded, R is hydrogen, R is fi-hydroxy or together R and R is keto, R" is lower alkyl (preferably methyl), and X is halogen; a process for preparing these new steroids; and new intermediates useful in said preparation.

The new 9ot-halo steroids of this invention are prepared by a series of steps which comprises: (a) interacting a steroid of the general formula wherein the 1,2-position is saturated or double-bonded, and R is as above defined, with a lower alkane sulfonyl halide at an elevated temperature in the presence of an organic base to yield the corresponding 9(l1)-dehydro derivative; (b) treating the 9(11)-dehydro derivative thus formed with a hydroxybrominating, hydroxychlorinating or hydroxyiodating agent to yield the corresponding 9abrorno (or 9a-chloro or 9rx-i0d0) llfl-hydroxy derivative; (c) either oxidizing the 9a-bromo (or 9a-Chl010 or 9% iodo) llfi-hydroxy derivative thus formed, if desired, to the corresponding ll-keto derivative, or treating with the salt of a strong base and weak acid to yield the corresponding 96,11B-epoxy derivative; (:17) treating the 95,11,8- epoxy derivative with a hydrogen halide to yield a 9dhalo llfl-hydroxy derivative; and (e) if desired, oxidizing the 9a-hal0 11,8-hydroxy derivative to the 9a-h21l0 11- keto derivative.

Among the suitable steroid reactants utilizable in the process of this invention may be mentioned the l2a-(lower alkyl)-llfi-hydroXy-progesterones (e.g. lZa-rnethyl-llflhydroxyprogesterone and lZa-ethyl-Ile-hydroxyprogesterone) and the lZalower alkyl)-A -pregnadiene-l1,8- ol-3,20-diones (e.g. l2cr-n1ethyl-A -pregnadiene-l1,B'-ol-3, 20-dione), which can be prepared by the process disclosed 3,l5l,l35 Patented Sept. 29, 1%64 I (EH3 (3H3 $113 C=O QH $=O I H0 of /i 5 0103 l X X 0: O

(II) X=Br (IV) X=Br (III) X=Ol (V) X=Cl (VI) X=F i ([3113 O J HX (VII) (VII) X=F (III) X= Cl To prepare the new 9(11)-dehydro intermediates of this invention one of the starting steroids is interacted with a lower alkane sulfonyl halide (cg. rnesyl chloride) at an elevated temperature in the presence of an organic base, such as pyridine, the reaction preferably being conducted in an organic solvent of high dielectric constant such as dimethvlforrnamide for the steroid reactant.

The 9(1l)-dehydro intermediate thus formed is then treated with a brominating or chlorinating agent in the presence of water and an acid of low nucleophilicity (e.g. perchloric acid). The preferred brominating agents are N-bromamides and N-bromimides of carboxylic acids. Suitable brominating agents include the N-bromamides of lower alkanoic acids (e.g., N-bromacetamide), the N- bromimides of lower alkanedioic acids (e.g. N-bromosuccinimide), and dibromodimethylhydantoin. Suitable chlorinating agents include the chloro analogues of the bromo compounds listed hereinbefore. The reaction is preferably conducted in an aqueous inert organic solvent, such as an alcohol or ether.

The reaction results in the production of a 9ot-bTOII1O (or chloro) llfi-hydroxy steroid, which can then either be oxidized by treatment with an oxidizing agent such as a hexavalent chromium compound (e.g. chromic acid) to the corresponding 9a-bromo (or chloro) ll-keto derivative; or converted to the corresponding 95,11B-epoxy derivative by treatment with a basic reagent such as an alkali metal salt of a lower fatty acid in a lower alcohol (e.g. an alkali metal acetate in ethanol), or with an alkali metal carbonate, dicarbonate, or hydroxide.

The 95,11fi-epoxy derivative can then be converted to the corresponding 9a-halo-11/8-hydroxy derivative by treatment with the desired hydrogen halide (i.e. hydroiodic acid, hydrobromic acid, and preferably hydrochloric acid and hydrofluoric acid). These 9oc-halo-11fi-hydroxy derivatives can in turn, if desired, be oxidized to the corresponding 9u-halo-11-keto derivatives by treatment with an oxidizing agent such as a hexavalent chromium compound (e.g. chromic acid).

The 9a-halo-1lfi-hydroxy (or ll-keto) steroids of this invention are physiologically active compounds which possess anti-inflammatory and especially progestational activity. Thus, these new steroids of this invention can be administered instead of, and in the same manner as progesterone in the treatment of uterine bleeding. It has been surprisingly found that the 12u-alkylated steroids of this invention are many times more active as pro'gestational agents than are the corresponding 12-unsubstituted derivatives. Thus, whereas 9a-chloro-1lp-hydroxy-progesterone possesses one-fourth the activity of progesterone in the Clauberg (McPhail) modification immature rabbit uterus test, 12a-methyl-9a-chloro-1lo-hydroxyprogesterone has the same to twice the activity of progesterone in the same test. l2a-methyl-9a-chloro-1lfl-hydroxyprogesterone is, therefore, four to eight times more active a progestational agent than is 9oc-chloro-1lfl-hydroxyprogesterone.

The following examples illustrate the preparation of the starting materials used in the process of this invention (all temperatures being in centigrade):

EXAMPLE A JZOL-MethyI-IJ-Ketoprogesterone 3,20-Bisethylene Ketal (a) Preparation of 9a-flu0r0-1Z-ketopragesterone 3,20- bis-ethylene ketal.-A mixture of 10 g. of 90c-fl11010-11- ketoprogesterone, 350 ml. of benzene, 80 ml. of ethylene glycol and 200 mg. of paratoluene-sulfonic acid monohydrate is refluxed with stirring for 72 hours. The reaction mixture is then cooled to room temperature and neutralized with sodium bicarbonate solution. The phases are separated and the aqueous layer reextracted with additional amounts of benzene. The combined benzene extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The crude residue on crystallization from acetone-hexane yields about 11 g. of the essentially pure bis-ethylene ketal melting at about 179-182. Recrystallization of this material from methanol gives an analytical sample melting at about 189-190.

(b) Preparation of Hot-methyl -11 -ketpr0gesterone 3,20-bis-ethylene ketaL-A solution of 9a-fluoro-l1-keto progesterone 3,20-bis-ethylene ketal g.) in benzene (100 ml.) is treated with an ethereal solution of lithium methyl (150 ml., 13.5 mg. of lithium metal/ml) The solution is stirred for 4 hours at room temperature and then the excess lithium methyl is decomposed by the addition of ice. Chloroform (300 ml.) is added, and the mixture is washed several times with water, dried over sodium sulfate and evaporated in vacuo. Trituration of the residue with hexane gives about 4.2 g. of 12a-rnethyl-11-ketoprogesterone 3.20-bis-ethylene ketal, M.P. about 135- 138". A second crop of crystals (about 2.4 g., M.P. about 124-l30) is obtained on concentrating the hexane mother liquor. Crystallization from methanol gives an analytical sample melting at about 139-142".

Similarly, by substituting an equivalent amount of lithium ethyl for the lithium methyl in the procedure of Example A, l2a-ethyl-11-ketoprogesterone 3,20-bis-ethylene ketal is obtained.

.at 75-80 for one hour.

4- EXAMPLE B 1 2 a-M ethy l-A -Pregnad Eerie-3 ,1 1 ,20-T ri one 3,20-Bis-Ethylene Ketal By substituting an equal amount of 9oc-fluoro-A -pregnadiene-S,1l,20-trione for the steroid reactant in the procedures of Example A, 1201 methyl A pregnadiene- 3,11,20-trione, 3,20-bis-ethylene ketal is obtained.

EXAMPLE C 12m-Methyl-1 1 5-H ydroxy progesterone 3,20-Bz's-Ethylene Ketal A solution of 1 g. of l2a-methyl-ll-ketoprogesterone 3,20-bis-ethylene ketal is 50 ml. of dry tetrahydrofuran is heated under reflux with 1 g. of lithium aluminum hydride for 18 hours. Ice is added to the cooled solution to decompose excess reagent and then a saturated aqueous solution of sodium sulfate is added with stirring until the precipitated aluminum salts are formed into a slurry. The clear ether solution is decanted off and the inorganic material is washed twice With chloroform. The combined organic extracts are dried over sodium sulfate and then evaporated in vacuo. The residue is dissolved in 10 ml. benzene and absorbed on a column of 30 g. of alumina. Elution with benzene (900 ml.) and chloroform-benzene (1:9, 500 ml), followed by crystallization from acetonehexane, yields 12oc-rnethyl-1lfi-hydroxyprogesterone 3,20- bis-ethylene ketal (about 660 mg.) melting at about 169-175". Crystallization from acetone-hexane afford an analytical sample which melts at about 177-170".

Similarly, by substituting 1 g. of 12a-ethyl-l1-ketoprogesterone 3,20-bis-ethylene ketal or 12ot-methyl-A pregnadiene-3,11,20-trione 3,20-bis-ethylene ketal for the 12et-methyl-1l-ketoprogesterone 3,20-bis-ethylene ketal in the procedure of Example C, 12a-ethyl-1lB-hydroxyprogesterone 3,20-bis-ethylene ketal and 12a-methyl-A pregnadiene-l1/8-ol-3,20-dione 3,20-bis-ethylene ketal are obtained respectively.

EXAMPLE D 1 2 u-Methy l-] 1 [8-H ydroxy progesterone A solution of 1.4 g. of 12c1-methyl-1lfi-hydroxyprogesterone 3,20-bis-ethylene ketal in 30 ml. of methanol and 3 ml. of 8% sulfuric acid is heated under reflux for one hour. The mixture is diluted with water, the precipitated solid collected and crystallized from chloroformmethanol to give about 1.1 g. of l2a-methyl-1lo-hydroxyprogesterone, M.P. about 235-238". Crystallization from chloroform-methanol gives an analytical sample melting at about 238-248.

Similarly, 12a-ethyl-1lfl-hydroxyprogesterone 3,20-bis ethylene ketal and 1Za-methyI-A -pregnadiene--01-3, 20-dione 3,20-bis-ethylene ketal can be hydrolyzed to 12methyl-llfl-hydroxyprogesterone and 12a-methyl-A -pregnadiene-l lfi-ol-3,20-dione respectively.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 12a-Methyl-A -Pregnadiene-3,20-Di0ne (I) A solution of 1.1 g. of IZa-rnethyl-llfi-hydroxyprogesterone in 21 ml. of dimethylformamide, 2.1 ml. of anhydrous pyridine and 2.1 ml. of mesyl chloride is heated The solution is then cooled, dlluted with Water, and the organic material extracted .With chloroform. The chloroform is washed several times with water, dried over sodium sulfate and the solvent removed in vacuo. The residue (about 1.02 g.) is dissolved in 25 ml. of benzene and absorbed in 35 g. of acid-washed alumina. Elution with hexane-benzene (1:1) and benzene followed by crystallization from acetone-hexane yields about 665 mg. of 12a-methyl-A pregnadiene-3,20-dione, M.P. about -142. A second crystalllzation from acetone-hexane afiords an analytical sample melting at about l44145; [a] =181 (c. 0.89 in (EH k111i; 238 my (17,000); k551i? 5.85, 5.95, 6.17

Analysis.-Calcd. for 0, 11, 0 (326.46): c, 80.93; H, 9.26. Found: C, 80.93; H, 9.30.

Similarly, 12a-ethyl-1lp-hydroxyprogesterone and 12amethyl-A -pregnadiene-115-ol-3,20-dione can be converted to 1ZwethyI-A -pregnadiene-3,20-dione and 1Zu-methyl-A -pregnatriene3,2O-dione, respectively.

EXAMPLE 2 9ocBi0i710I 1 0H y droxy-I 2 a-M ethy l progesterone (I I To a solution of 200 mg. of 12a-methyl-A -pregnadiene-3,20-dione in 20 ml. of dioxane and 11.5 ml. of 0.3 N-perchloric acid is added 125 mg. of N-bromoacetamide. The reaction mixture is allowed to stand in the dark for one hour at room temperature. After adding a few drops of sodium bisulfite solution, the mixture is diluted with chloroform (50 ml.). The chloroform-dioxane solution is washed with aqueous sodium bicarbonate and then with water, dried over sodium sulfate and the solvent removed in vacuo. Trituration of the oily residue with methanol yields about 84 mg. of the bromohydn'n which melts at about 125l30 (dec.); [Ct] +174- (c. 0.57 in CHC'1 .;1-;-,, 24.3 my. (13,500); rag? 3.00, 5.88, 9.13

Analysis.-Calcd. for C H O Br (423.38): C, 62.41; H, 7.38; Br, 18.88. Found: C, 62.51; H, 7.32; Br. 18.34.

EXAMPLE 3 9a-Clzl0r01lfi-Hydroxy-IZ oc-M ethyl progesterone (III) Following the procedure of Example 2, but substituting 130 mg. of N-chlorosuccinimide for the N-bromoacetamide, there is obtained 9a-chloro-1lB-hydroxy-12ocmethylprogesterone.

EXAMPLE 4 9a-Bi0m0-1 I-Keto-12a-Methylpr0gester0ne (IV) M23; 239 m (e =12,400); H132 5.88, 5.99, 6.20 EXAMPLE 5 973,1 1 ,B-Epaxy-I Zea-M ethyl progesterone (VII) A solution of 9u-bromo-1lfi-hydroxy-l2ot-methylprogesterone (42 mg.) in 2 ml. of methanol is stirred under nitrogen with 0.18 ml. of aqueous potassium carbonate. The reaction mixture is diluted with water, the precipitated solid collected and crystallized from acetonehexane. The methyl oxido compound (about 17.3 mg.) so obtained has a melting point of about 125-127"; [0L]n+38.6 (0.63 in CHCl max.

Analysis.Calcd. for C I-1 0 (342.46): C, 77.15; H, 8.83. Found: C, 77.00; H, 8.33.

EXAMPLE 6 9a-Flu0ro-1l fl-Hydroxy-IZa-Methylprogestemne (VIII) A solution of 60 mg. of 9B,1lB-epoxy-12a-methylprogesterone in 9.5 m1. of chloroform and 0.5 ml. of alcohol is treated at 0 with anhydrous hydrogen fluoride until a substantial layer of hydrogen fluoride has formed. The mixture is kept at 0 for one hour and twenty minutes with stirring and then neutralized by addition of a suspension of sodium bicarbonate in water. After separation of the chloroform layer, the latter is washed with water, dried over sodium sulfate and the solvent removed in vacuo. The residue is dissolved in 5 ml. of benzene and 10 ml. of hexane and the solution chromatographed over a column of 2.2 g. of acid-washed alumina. Elution with 550 ml. of benzene-hexane (1:2) furnishes about 30 mg. of 11a,12[3-dimethyl-A -19-norpregnatriene-3,20-dione. Continued elution of the column with 600 ml. of benzene and 400 ml. of benzenechloroform (9:1) furnishes about 9 mg. of 9oz-fiu0r0- IZa-methyl-llfi-hydroxyprogesterone, which after recrystallization from acetone-hexane has the following properties: M.P. about 228229; [M +147 (0., 0.32 in Cl-iCl Nuiol max. 5-90; 6-10;

Analysis.Calcd. for C H O F (362.46): C, 72.90; H, 8.62. Found: C, 72.97; H, 8.68.

EXAMPLE 7 .9a-Chloro-I1fi-HydroxyJZoa-Methylprogesterone (III) Analysis.-Calcd. for C H O Cl (378.97): C, 69.73; H, 8.24. Found: C, 69.43; H, 8.25.

EXAMPLE 8 9a-Flu0r0-1 I -Ket0-I1 Za-M ethyl progesterone VI Following the procedure of Example 4, but substituting 9a-fluoro-11fl-hydroxy- 12cc -methylprogesterone for the bromo steroid in the example, there is obtained 9oc fluoro-l l-keto-l Za-methylprogesterone.

EXAMPLE 9 9u-Chl0r0-11 -Ket012a-Methylprogesterone (V) Fol-lowing the procedure of Example 4, but substituting 9zxChlOT0-l 1B-hydroxy 12oz methylprogesterone for the bromo steroid in the example, there is obtained chloro-1-1-keto-l2a-methylprogesterone.

What is claimed is:

1. A compound selected from the group consisting of steroids of the formula and the 1,2-dehydro derivatives thereof, wherein R is hydrogen, R is p-hydroxy, R is lower alkyl, and X is halogen.

2. 9ot-halo-l 1 8-l1ydroxy-12u-methylprogesterone.

3. 9ot-chloro-l 1 ,B-hydroxy-12ot-methylprogesterone.

4. 9oc-fluoro-llfi-hydroxyd2a-methylprogesterone.

References Cited in the file of this patent UNITED STATES PATENTS 2,852,511 Fried Sept. 16, 1958 

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF STEROIDS OF THE FORMULA 